Regenerative Medicine Changing the Game in Orthopedics. Trevor Bullock, DO

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1 Regenerative Medicine Changing the Game in Orthopedics Trevor Bullock, DO April 1st, 2017

OBJECTIVES Understand the basic principles behind the science of treatments with platelet-rich plasma and bone marrow concentrate injections for various

2 OBJECTIVES Understand the basic principles behind the science of treatments with platelet-rich plasma and bone marrow concentrate injections for various orthopedic problems Learn about current research regarding treatment with stem cells in orthopedics Understand which patients would be ideal candidates for treatment

3 DISCLOSURES Teaching consultant for Arthrex

4 SPOILER ALERT! Basic science and in vitro studies for PRP and BMC demonstrate the release of growth factors and their potential role in healing Robust trials and in vivo studies are scarce and sometimes have conflicting results Lack of strong clinical evidence is due to the wide variety of PRP/BMC preparations, extractions, cell counts, growth factor yields or activity, lack of post-procedure protocols Differences in tissue types, injuries and patient comorbidities also contribute to the broad range of study results Despite all of this, there continues to be extensive utilization of these products

5 THE PROBLEM 45 year old active male with moderate osteoarthritis of his knees Continued pain despite: Weight loss Home Exercises /Physical Therapy Activity modification NSAIDs / Glucosamine /Chondroitin Cortisone Injection Viscosupplementation Unloader Brace Prior arthroscopic debridement with microfracture

6 CASE 1 Too young to replace the knee What can you do for him?

7 THE PROBLEM: Anti-inflammatory Medications Glucosamine/Chondroitin Cortisone Injection Viscosupplementation Steroids These focus on relief of symptoms, rather than improving the biochemical environment and/or structure of joints

8 What if he could significantly delay or even prevent progression to this

9 WHAT IS REGENERATIVE MEDICINE? Scientific field that focuses on new approaches to the process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function. - Utilize your body s stem cells and blood platelets for healing and repair - Bone marrow concentrate injections - Platelet Rich Plasma injections

10 WHEN DO WE USE REGENERATIVE MEDICINE? Patients coping with arthritis, sports injuries, tendon strains, sprained ligaments, muscle injuries and more Faster healing as well as improved functionality both are possible with innovative, cutting- edge adult stem cell and PRP procedures.

11 WHAT HAS BENEFITED FROM THESE PROCEDURES? Osteoarthritis Meniscus tears Chronic tendinitis/tendinosis Labral tears of the hip or shoulder Partial rotator cuff tears Tennis elbow Plantar Fasciitis Trochanteric Bursitis/Gluteus Medius Tendinopathy Sacroiliac (SI) Joint Dysfunction Degenerative Disc Disease Avascular necrosis

12 THOUGHTS ON STEM CELLS?

13 WHAT ARE STEM CELLS? Undifferentiated immature cells Found throughout your body

15 STEM CELLS Stem Cells Prenatal (embryonic) Postnatal (adult)

16 POSTNATAL (ADULT) STEM CELLS More readily available Less political / ethical ramifications Multiple sites are available for isolation of adult stem cells, including: adipose peripheral blood periosteum synovium bone marrow skeletal muscle umbilical cord dental pulp.

17 STEM CELLS Stem Cells Prenatal (embyonic) Postnatal (adult) Mesenchymal Stem Cells (MSCs)

18 MESENCHYMAL STEM CELLS (MSCS) Stem Cells of interest in orthopedics 1. Capacity for transformation into bone, fat and cartilage cells (help to regrow cartilage) 2. Induce production of specific T helper cells which produces an anti-inflammatory state Decreased interferon gamma (inflammatory) Increased Interleukin 4 (anti-inflammatory) Capacity for self-replication Immunomodulatory properties?

19 MSCS HOMING TO INJURY SITE Damaged Cartilage MSCs

20 STEM CELLS Stem Cells Prenatal (embryonic) Postnatal (adult) Mesenchymal Stem Cells (MSCs) Bone Marrow Adipose tissue

21 BONE MARROW INJECTIONS Most abundant source of MSCs Most studied in literature and first available for use Obtained through simple bone marrow aspiration Good for treating multiple orthopedic problems for a potent effect

22 BONE MARROW ASPIRATION

24 BONE MARROW

25 BONE MARROW CONCENTRATE Contains mesenchymal stem cells (MSCs), hematopoetic stem cells, platelets (containing growth factors), and cytokines Anti-inflammatory and immunomodulatory properties can facilitate regeneration of tissue Available for a same-day procedure with minimal manipulation of cells Compliant with FDA restrictions Several publications report ease of use, strong safety profile Sampson S., et. Al. Autologus Bone Marrow Concentrate: Review and Application of a Novel Intra-Articular Orthobiologic for Cartilage Disease. The Physician and Sportsmedicine :3

26 BONE MARROW CONCENTRATE

29 ADIPOSE AS STEM CELL SOURCE Obtain from love handles No culturing Claims of 1000x stem cell concentration as bone marrow Does not have as many mesenchymal stem cells as bone marrow Over 1700 peer reviewed papers published Use as a scaffolding for bone marrow stem cells

30 LIPOASPIRATE

31 INJECTION Ultrasound guidance is utilized for targeted placement of the injection of fat tissue and bone marrow concentrate

32 PRP/BMC AND LIPOASPIRATES The combination of fat with PRP (or BMC) has been reported to enhance the tissue acceptance of autologous grafts in thousands of cases in the aesthetic literature. Numerous conditions can benefit from this grafting technique, including tendinoses, partial to full thickness tendon tears, interstitial tendon tears, ligament tears, muscle strains/fibrosis, osteoarthritis, and disc damage. Abuzeni P, Alexander RW. Enhancement of autologous fat transplantation with platelet rich plasma. Am J Cosmet Surg. 2001;18: Mizuno H. Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sch. 2009;76: Guilak F, Estes B, Diekman B, et al Nicolas Andry Award: multipotent adult stem cells from adipose tissue for musculoskeletal tissue engineering. Clin Orthop Relat Res. 2010;9:

34 BMC EVIDENCE

$(microfracture) Osteochondral autograft transfer Osteochondral allograft Autologous chondrocyte implantation$

35 ARTICULAR CARTILAGE Limited ability to self-repair after injury Current methods to treat: Bone Marrow stimulation (microfracture) Osteochondral autograft transfer Osteochondral allograft Autologous chondrocyte implantation (ACI)

ARTICULAR CARTILAGE DEFECTS (2010) Nejadnik, et al compared treatment of knee cartilage defects with bone marrow-derived stem cells (BMSCs) and autologous chondrocyte implantation (ACI) Improvement

36 ARTICULAR CARTILAGE DEFECTS (2010) Nejadnik, et al compared treatment of knee cartilage defects with bone marrow-derived stem cells (BMSCs) and autologous chondrocyte implantation (ACI) Improvement in patient s quality of life in both groups No significant difference between BMSC and ACI group in terms of clinical outcomes except for physical role functioning, with greater improvement in BMSC group. BMSC group is less invasive, normal articular cartilage is not damaged, one less surgery, less cost Nejadnik H., et al. Autologous bone marrow-derived mesenchymal stem cells versus autologuous chondrocyte implantation: an observational cohort study. AJSM. 2010; 38:

37 KNEE ARTICULAR CARTILAGE (2013) Kim et al performed BMC injections (with adipose tissue) in 41 patients (75 knees) with OA of the knee. They found significant improvement in pain and function in patients with KL Stage 1 3 arthritis

38 KNEE ARTICULAR CARTILAGE (2015) Oliver et al evaluated clinical efficacy of autologous intraarticular BMC and lipoaspirate as treatment option for the knee Evaluated treatment for 70 patients diagnosed with Kellgren- Lawrence Stage 2-4 Knee OA at 90 and 180 days Function and Symptoms monitored through Knee Injury and Osteoarthritis Outcome Score (KOOS) - Found significant improvements in Pain, ADLs, Symptoms, Quality of Life and Sports/Recreational activity Oliver K., et. Al. Clinical Outcome of Bone Marrow Concentrate in Knee Osteoarthritis. Journal of Prolotherapy. 2015; 7:e937-e946

39 Systematic Review, 11 studies - 5 prospective, 1 retrospective, 2 case series, 3 case reports - Main finding of this review was good to excellent overall outcomes reported with the use of BMAC for the treatment of early knee OA and moderate chondral defects - Level of evidence varied from 2 to 4

40 Joint Capsule Proximal Tibia Distal Femur Medial Mensicus

41 CARTILAGE REGENERATION? Documented case reports of increased cartilage and meniscus volume on MRI

REFRACTORY TENNIS ELBOW Already demonstrated efficacy with PRP (51 pts) over cortisone injections (49 pts) at 2 year follow up (double blind, placebo controlled study) Gosens T., et. Al. Ongoing Positive Effect of PRP versus Corticosteroid Injection in Lateral Epicondylitis: A Double Blind Randominzed Controlled Trial with 2 Year Follow up.

42 REFRACTORY TENNIS ELBOW Already demonstrated efficacy with PRP (51 pts) over cortisone injections (49 pts) at 2 year follow up (double blind, placebo controlled study) Gosens T., et. Al. Ongoing Positive Effect of PRP versus Corticosteroid Injection in Lateral Epicondylitis: A Double Blind Randominzed Controlled Trial with 2 Year Follow up. AJSM : BMC treatment has shown significant improvements in pain and function in short to medium term follow-up Singh et. Al. Injection of bone marrow concentrates for treatment of refractory tennis elbow. Saudi Jounal of Sports Medicine :

43 ROTATOR CUFF TEARS BMC used as an adjunctive therapy during rotator cuff repair enhanced the healing rate and improved quality of the repaired surface. BMC treated 45/45 (100%) treated healed by 6 months 39/45 (87%) had intact rotator cuff at 10 years Non-BMC treated 30/45 (67%) healed by 6 months 20/45 (44%) had intact rotator cuff at 10 years Hernigou P et. al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arhroscopy improves healing and prevents further tears: a case-controlled study. International Orthopaedics :

44 SUPRASPINATUS TENDINOPATHY Supraspinatus Defect Humeral Head

45 SUPRASPINATUS TENDINOPATHY

46 OTHER AREAS OF BENEFIT BMA Treatment of nonunion fractures 82% (9/11) had healing after 6 months Improvement in pain and function Braly HL, et. al. Percutaneous autologus bone marrow injection in the treatment of distal meta-diaphyseal tibial nonunions and delayed unions. J Orthop Trauma : Lumbar Discogenic Pain 80% (21/26) had significant reductions in pain and impairment through 12 months 40% (8/20) were noted to have rehydration of treated discs on MRI Pettine K et. al. Percutaneous Injection of Autologus Bone Marrow Concentrate Cells Significantly Reuces Lumbar Discogenic Pian Through 12 Months. Stem Cells :

OTHER AREAS OF BENEFIT Avascular necrosis Retrospective review over 13 years 594 hips treated with core decompression combined with bone marrow concentrate Significant improvements in pain and

47 OTHER AREAS OF BENEFIT Avascular necrosis Retrospective review over 13 years 594 hips treated with core decompression combined with bone marrow concentrate Significant improvements in pain and function of treated patients Only 17% progressed to hip replacement (40% with core decompression alone) Houdek M., et. Al. Stem cell treatment for avascular necrosis of the femoral head: current perspectives. Stem Cells Cloning. 2014; 7:65-70

48 PLATELET-RICH PLASMA

49 The concept of PRP is using your own platelets and growth factors to heal the injured site. transforming growth factor, insulin-like growth factor, fibroblast growth factor, and platelet- derived growth factor. We take a sample of your blood and place spin it down in a centrifuge to obtain a concentrated sample of growth factors can be 5 to 10 times greater than usual. Platelet is activated upon injection Releases growth factors Increases anabolic signaling

50 PROCEDURE FOR PRP Collect 30-90ml of blood Centrifuge collect 3-7ml PRP Inject to specific site

51 DOES PRP WORK? Significant Difference Peerbooms, AJSM, 2010 Kon, KSSTA, 2010 Filardo, KSSTA, 2010 Radice, Arthroscopy, 2010 Wang-Saegusa, AOTS, 2011 Thanasas, AJSM, 2011 Gosens, AJSM, 2011 No Difference Silva, KSSTA, 2009 De Vos, JAMA, 2010 Vogrin, ESR, 2010 Creaney, BJSM, 2011 DeJonge, AJSM, 2011 Schepull, AJSM, 2011 PubMed article search: 8,200

52 NOT ALL PRP CREATED EQUAL: Medium platelet numbers Full leukocytes Erythrocytes Concentrated platelet numbers Varying leukocyte composition Varying erythrocytes Custom PRP concentrations Low platelets Low leukocytes Erythrocytes Low platelets No leukocytes No erythrocytes

53 PRP RE-FORMULATED PER INDICATION PRP Platelets Growth factors WBCs RBCs Uses: Tendinopathy Ligament and Tendon healing OA Erythrocytes Platelets Leukocytes

54 ROLE OF LEUKOCYTES In contrast to platelets, leukocytes contain and produce cytokines that are catabolically active and promote inflammation Promote chemotaxis, proliferation and differentiation of cells Induce extracellular matrix production and angiogenesis Release inflammatory cytokines IL-1β, IL-6, INF-gamma,TNF-α Reactive oxygen species

55 LP VS LR-PRP LP-PRP has been shown in numerus studies to be ANTI-inflammatory Increased IL-4, IL-10 LR-PRP is PRO-inflammatory Increased IL-1Beta, IL-6, IFNGamma, TNF-Alpha

56 EFFICACY OF PRP The efficacy of PRP treatment improves with tailored formulations for specific conditions Tendinopathy OA Muscle Injury LR-PRP LP-PRP PPP? Braun, et. Al. The effect of Platelet-Rich-Plasma Formulations and Blood Products on Human Synoviocytes

MSCS AND PRP It has been demonstrated that by combining PRP and MSCs in vitro a 10-fold increase stem cell activity Mishra A, Tummala

Tissue Eng Part C Methods. 2009;15:431-435.

begins at a 4- to 5-fold increase in platelet numbers Haynesworth SE, Kadiyala S, Liang LN: Mitogenic stimulation of human

57 MSCS AND PRP It has been demonstrated that by combining PRP and MSCs in vitro a 10-fold increase stem cell activity Mishra A, Tummala P, King A, et al. Buffered platelet-rich plasma enhances mesenchymal stem cell proliferation and chondrogenic differentiation. Tissue Eng Part C Methods. 2009;15: Haynesworth et al showed that human mesenchymal stem cell proliferation is proportional to the platelet concentrations in PRP, and it begins at a 4- to 5-fold increase in platelet numbers Haynesworth SE, Kadiyala S, Liang LN: Mitogenic stimulation of human mesenchymal stem cells by platelet release suggest a mechanism for enhancement of bone repair by platelet concentrates. Presented at the 48th Meeting of the Orthopaedic Research Society, 2002, Boston, MA Future studies needed in this area

58 REGENERATIVE CONSULTATION Consult will assess if patient is a candidate for Stem Cell/ PRP We ask to bring any imaging. MRI not always necessary. Sometimes we may have to stop certain medications for 2-3 weeks prior to procedure and for 6 weeks after procedure. - Steroids, NSAIDS, Aspirin, Statins and ACE inhibitors

59 PATIENTS WHO ARE NOT CANDIDATES Patients with blood borne cancers (lymphoma or leukemia) or other malignancies Patient with any current infection Patients on high dose blood thinners Patients with multiple medical issues may not be good candidates

60 WHAT DETERMINES HOW A PATIENT WILL RESPOND TO TREATMENT? 1. Severity of the problem? 2. Healing potential of the patient Age, medical problems, medications, social history, etc. 3. Physician treatment Product used, collection of PRP/BMC, machine used to process, formulation (cell content), separation into syringes, placement of injection(s) 4. After Treatment?

61 RECOVERY FOR ALL PROCEDURES The total procedure time takes approximately minutes, including preparation, treatment and recovery time. Performed in the medical office without general anesthesia or hospital stays, and without a prolonged recovery period. Most patients have increased pain for 3-5 days after the procedure Most patients return to their jobs or usual activities within a couple of days.

62 RECOVERY FOR ALL PROCEDURES The healing and repair usually takes 2-3 months but improvement is usually noted before that time. Follow up appt 4-6 weeks after the procedure May decide to do follow up PRP injections

63 HOW CAN WE OPTIMIZE HEALING?

64 LOWER EXTREMITY REHAB PROTOCOL

65 COST Insurance does not cover the procedures at this time. There is no national standard for cost in the United States

66 THE FUTURE There are more than 4627 adult stem cell clinical trials approved by the US Food and Drug Administration that are currently being conducted with ongoing recruitment Currently considered investigational Coverage from insurance companies in the future? - Accessed September 1, 2014

67 QUESTIONS THAT NEED TO BE ANSWERED Protocol for maximum efficacy? Dose/type of cells for maximum efficacy? What is the quality of tissue that is regenerated? What are the most important biologic factors of a patient that can affect outcome of treatment? What are the long-term outcomes for some of these procedures

68 SUMMARY Low risk procedures that are showing great potential for treatment of multiple orthopedic issues. There are a lot of accumulating basic science and preclinical studies supporting the benefits of stem cell therapy. Clinical trials demonstrating the value of these new approaches are growing Many questions remain regarding dose, protocols and long term benefits of the procedures

69 OTHER REFERENCES Filip S, English D and Mokry J (2004). Issues in stem cell plasticity. J Cell Mol Med 8 (4): Filip S, Mokrý J, Hruška I (2003) Adult stem cells and their importance in cell therapy. Folia Biol.(Prague) 49: Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived Stem Cells for Regenerative Medicine Circ Res. 100: Abuzeni P, et al. Enhancement of autologous fat transplantation with platelet rich plasma. Am J Cosm Surg. 2001;18:9-71. Counsel,P., et al. Cell Therapy in Joint Disorders. Sports Health 2015 Vol 7 (1): Molloy T,Wang Y, Murrell G. The roles of growth factors intendon and ligament healing. Sports Med 2003;33: Stem cell therapy for cartilage regeneration in osteoarthritis.koelling S1, Miosge N. Expert Opin Biol Ther Nov;9(11): REVIEW - Mesenchymal stem cells in arthritic diseases. Faye H Chen and Rocky S Tuan, Arthritis Research & Therapy 2008, 10:223 Sampson S., et. Al. Autologus Bone Marrow Concentrate: Review and Application of a Novel Intra-Articular Orthobiologic for Cartilage Disease. The Physician and Sportsmedicine :3 Oliver K., et. Al. Clinical Outcome of Bone Marrow Concentrate in Knee Osteoarthritis. Journal of Prolotherapy. 2015; 7:e937-e946 Nejadnik H., et al. Autologous bone marrow-derived mesenchymal stem cells versus autologuous chondrocyte implantation: an observational cohort study. AJSM. 2010; 38: Gosens T., et. Al. Ongoing Positive Effect of PRP versus Corticosteroid Injection in Lateral Epicondylitis: A Double Blind Randominzed Controlled Trial with 2 Year Follow up. AJSM : Singh et. Al. Injection of bone marrow concentrates for treatment of refractory tennis elbow. Saudi Jounal of Sports Medicine : Hernigou P et. Al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arhroscopy improves healing and prevents further tears: a case-controlled study. International Orthopaedics : Braly HL, et. Al. Percutaneous autologus bone marrow injection in the treatment of distal meta-diaphyseal tibial nonunions and delayed unions. J Orthop Trauma : Pettine K et. Al. Percutaneous Injection of Autologus Bone Marrow Concentrate Cells Significantly Reuces Lumbar Discogenic Pain Through 12 Months. Stem Cells : Houdek M., et. Al. Stem cell treatment for avascular necrosis of the femoral head: current perspectives. Stem Cells Cloning. 2014; 7:65-70

Most cells in the human body have an assigned purpose. They are liver cells, fat cells, bone cells,

What is a Stem Cell? Most cells in the human body have an assigned purpose. They are liver cells, fat cells, bone cells, and so on. These cells can replicate more of their own kind of cell, but they cannot